NM_000077.5:c.306G>T

CDKN2A · NP_000068.1:p.(Ala102=) · NM_000077.5

GRCh37: chr9:21971052 C>A · GRCh38: chr9:21971053 C>A

Gene: CDKN2A Transcript: NM_000077.5

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.5

Protein

NP_000068.1:p.(Ala102=)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) in exon 2 of CDKN2A.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).

SpliceAI predicts no splicing impact (max delta score 0.00), and in silico tools REVEL (0.182) and BayesDel (-0.230) support a benign interpretation (BP4_Supporting, BP7_Supporting).

ClinVar records show two submissions of Uncertain significance and one submission of Likely benign; no pathogenic classification has been reported.

No functional studies, case reports, segregation data, or de novo observations are available for this variant. All four PMIDs reviewed (25394175, 26389258, 26389333, 28492532) are general guidance or methodology papers that do not mention the specific variant.

The net evidence profile (1 supporting pathogenic criterion, 2 supporting benign criteria) is consistent with a variant of uncertain significance.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 requires a different nucleotide change producing the same missense amino acid change as a known pathogenic variant. This is a synonymous variant; no alternate nucleotide change at the same codon could produce a different missense change.
PS2	Not met	No de novo data are available for this variant. No publications report de novo occurrence of NM_000077.5:c.306G>T.
PS3	Not met	No functional studies assessing the biological effect of NM_000077.5:c.306G>T have been identified in the literature. OncoKB lists this variant as having unknown oncogenic effect with no curated functional data.	oncokb
PS4	Not met	No case-control studies or multiple unrelated proband observations are available for this variant. No publications report affected individuals carrying NM_000077.5:c.306G>T.
PS5	Not met	No reputable source has classified this variant as pathogenic. ClinVar submissions include two VUS classifications (GeneDx, Invitae) and one Likely benign (Ambry Genetics); none classify as pathogenic.	clinvar
PM1	Not met	c.306G>T is a synonymous variant at codon 102 of CDKN2A. This position has not been identified as a mutational hotspot in cancerhotspots.org, nor does it fall within a recognized functional domain with enrichment of pathogenic variants and absence of benign variation. OncoKB shows unknown oncogenic effect.	oncokb
PM2	Met	NM_000077.5:c.306G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for allele frequency below 0.1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different missense change at the same residue that has already been established as pathogenic. c.306G>T is a synonymous variant (p.Ala102=) with no amino acid change; no pathogenic comparator at the same residue is applicable.	pm5_candidates
PM6	Not met	No de novo observations have been reported for this variant. No publications document a de novo occurrence of NM_000077.5:c.306G>T with confirmed maternity and paternity.
PP1	Not met	No segregation data are available for this variant. No family studies have been published.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. c.306G>T is a synonymous variant, not a missense change.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.182 (below pathogenic threshold), BayesDel score -0.230 (negative = benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These data do not support a pathogenic interpretation.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available for this variant. No case reports or clinical series describe individuals carrying NM_000077.5:c.306G>T with a phenotype specific for CDKN2A-associated disease.
PP5	Not met	No reputable source has classified this variant as pathogenic. ClinVar records show two submissions as Uncertain significance (GeneDx, Invitae) and one as Likely benign (Ambry Genetics). None classify as pathogenic.	clinvar
BA1	Not met	NM_000077.5:c.306G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_000077.5:c.306G>T is absent from population databases. The allele frequency is 0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous observations or observations in trans with a known pathogenic CDKN2A variant have been reported. Insufficient data to support BS2.
BS3	Not met	No functional studies demonstrating a benign effect have been identified. No variant-specific functional assays (e.g., splicing minigene, protein function) have been published for NM_000077.5:c.306G>T.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease. No family studies have been published for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. c.306G>T is a synonymous variant, not a missense change.
BP2	Not met	No phase data are available. No observations of this variant in trans with a pathogenic CDKN2A variant, nor in cis with a pathogenic variant, have been reported.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.182 (below 0.5 pathogenic threshold), BayesDel score -0.230 (negative = benign), and SpliceAI max delta score 0.00 (no predicted splicing alteration). These concordant in silico predictions support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in an individual carrying this variant. No data are available to suggest this variant is incidental to an alternative genetic diagnosis.
BP6	Not met	ClinVar submissions for NM_000077.5:c.306G>T include two Uncertain significance classifications (GeneDx, Invitae) and one Likely benign classification (Ambry Genetics). The majority classification is VUS; no consensus benign classification from a reputable source has been established.	clinvar
BP7	Met	NM_000077.5:c.306G>T is a synonymous variant (p.Ala102=) with no predicted splicing impact. SpliceAI max delta score is 0.00, indicating no effect on splice consensus sequences or creation of a new splice site. In silico predictors (REVEL 0.182, BayesDel -0.230) suggest the nucleotide position is not highly conserved.	spliceai revel bayesdel

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